Matt Harmon

13 Chapter one blood flow, increasing intracranial pressure. 21 In sepsis the increased metabolic demand of fever could exceed the hosts metabolic or cardiopulmonary capacities, exacerbating tissue hypoperfusion and tissue hypoxemia resulting in increased organ failure. 22 This can be exacerbated by sepsis induced cardiopulmonary disfunction. In addition, enhanced host defenses may directly cause collateral tissue injury. 22 In an lipopolysaccharide (LPS) model, exposure to hyperthermia increased neutrophil localization to the lungs potentially increasing the risk for lung injury. 15,23 Pathophysiology of the hypothermic response in sepsis. Hypothermia in sepsis is generally defined as a temperature below 36.0°C. Patients with hypothermic sepsis have substantially higher mortality rates compared to nonhypothermic septic patients. 24 Interventions targeting hypothermic septic patients could therefore potentially have a profound impact on clinical outcome. However, our understanding of the hypothermic response in sepsis is limited and mechanisms underlying the hypothermic response remain largely hypothetical. In light of the perceived immune benefits of fever, the fact that patients develop hypothermia during a severe infection is intriguing and has led to the assumption that hypothermia in sepsis is a result of some physiological or biochemical failure to produce or conserve heat. 25,26 However, body temperature changes during infection have been preserved throughout evolution arguing that both fever and hypothermia provide a survival advantage for vertebrates. 10 In line with this, experimental studies point to hypothermia representing an adaptive response in the face of severe inflammation. 10,26-28 Animals with more severe infections deliberately attempt to lower their body temperature compared to animals with less severe infections which attempt to increase body temperature. 29 Heat conserving or generating mechanisms are intact in hypothermic animals faced with endotoxin shock, indicating that hypothermia may not be a dysfunction of the thermoregulatory system. 30 A recent study found that the conversion from fever to hypothermia may be initiated as a strategy to prevent cellular hypoxia. 31 However, these studies have only been performed in rodents and comparing the thermodynamic response to infection between rodents and humans is difficult, due to differences in their respective thermoregulatory responses. 32 In contrast, clinical studies to date have mainly focused on impaired thermoregulation as a cause of hypothermia. Of note, interpreting results from observational studies in hypothermic septic patients is inherently difficult due to confounding. Patients with hypothermic sepsis are sicker in comparison to febrile septic patients and any observations in hypothermic patients may also be attributed to increased disease severity. 33,34